1. Field of the Invention
This invention relates to novel thrombin inhibiting bisamidine derivatives, their salts and hydrates and to a process for the preparation thereof. The compounds of this invention are useful under conditions of thrombosis, ischemia or stroke.
2. Description of the Art
Thrombosis can be regarded as a pathological condition where improper regulation of the hemostatic mechanism results in the formation of intravascular thrombi which may lead to tissue damage or death due to inadequate blood flow. This condition is a major cause of mortality and morbidity in humans. Thrombin plays many crucial roles in hemostasis and thrombosis The serine protease activity of thrombin is required for the cleavage of fibrinogen to fibrin polymer and also for platelet activation. In the presence of the coagulation factor XIIIa, this polymer undergoes crosslinking and forms the insoluble fibrin clot. The development of agents to inhibit thrombin generation and activity in prethrombotic situations could be useful for control of blood coagulation and could greatly aid in lowering the incidence of thrombus-induced myocardial and cerebral ischemia.
Substituted bisamidines of the Formula I are known intermediates in the preparation of certain anti-ulcer agents of the Formula II. U.S. Pat. Nos. 4,374,248 and 4,440,933 disclosed and claimed a series of I and II as anti-ulcer agents. ##STR1##
John E. Starrett, Jr., et al., in a reoently published article (J. Med. Chem., 32: 2204 (1989)) disclosed selected bisamidine containing imidazo[1.2-a]pyridines (Formula III) as a key intermediate in the preparation of antiulcer agents. ##STR2##
Okamoto, et al., U.S. Pat. No. 4,041,156 and Cleason, et al., U.S. Pat. No. 4,537,896 disclosed a number of arylsulfonyl arginine amides and p-guanidino phenyl alanine amides of the general Formula IV and V useful as thrombin inhibitors. ##STR3##
Bajusz, et. al., in Int. J. Pept. Protein Res., 2:217-221 (1978) discloses peptide aldehydes of the Formula VI which have thrombin inhibitory properties. ##STR4##
There is nothing in any of the foregoing references, to suggest the novel thrombin inhibitors bisamidine derivatives of the present invention.